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Requirement for GPR56 in islet adaptation to metabolic stress

Oladapo Olaniru, King's College London



Islet b-cells adapt to increased insulin resistance associated with obesity-induced metabolic stress by expanding their mass and increasing insulin output. Failure of β-cells to adapt appropriately leads to glucose intolerance and, in the longer term, type 2 diabetes. G-protein coupled receptors (GPCRs) are tractable drug targets, and we have demonstrated that GPR56 is activated by extracellular matrix collagen III to augment glucose-induced insulin secretion and protect β-cells from apoptosis. In this project, I  aim to address the hypothesis that activation of GPR56, the most highly expressed islet GPCR, offers a therapeutic target for maintaining functional β-cell mass in diabetes. 

Prior to Covid-19 lockdown, I successfully generated a β-cell specific GPR56 knockout mouse colony (GPR56b-KO) by crossing GPR56 floxed mice with non-inducible Ins1Cre mice. I have shown that these mice are phenotypically normal and do not exhibit impaired glucose tolerance. I placed GPR56b-KO mice and their wild type littermates on a high fat diet. They are now in their 16th week of high fat feeding and overtly obese and insulin intolerant, and I had planned to isolate islets for functional studies at this stage. However, I have extended the endpoint to 20 weeks of feeding, as I am still on furlough. I will use these mice (and subsequent cohorts) to determine whether GPR56 is important in β-cell adaptations to metabolic stress.


Grant awarded: £5,000

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